Asparagine endopeptidase: Difference between revisions
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'''Asparagine endopeptidase''' ('''AEP''', '''mammalian [[legumain]]''') is a [[Protease|proteolytic enzyme]] from C13 [[peptidase]] family which hydrolyses a peptide bond using the thiol group of a [[cysteine]] residue as a nucleophile (hence also called [[cysteine protease]]). It hydrolyzes substrates at the C-terminus of [[asparagine]] residues. Discovered in 1996 in beans, its homologues have been identified in plants, protozoa, vertebrates, and helminths. The enzyme has been implicated in several human diseases such as [[cancer]], [[atherosclerosis]] and [[inflammation]] .<ref name=" |
'''Asparagine endopeptidase''' ('''AEP''', '''mammalian [[legumain]]''') is a [[Protease|proteolytic enzyme]] from C13 [[peptidase]] family which hydrolyses a peptide bond using the thiol group of a [[cysteine]] residue as a nucleophile (hence also called [[cysteine protease]]). It hydrolyzes substrates at the C-terminus of [[asparagine]] residues. Discovered in 1996 in beans, its homologues have been identified in plants, protozoa, vertebrates, and helminths. The enzyme has been implicated in several human diseases such as [[cancer]], [[atherosclerosis]] and [[inflammation]] .<ref name="Zhang 2016"/> It can be detected in spleen, liver, brain, testis tissue and heart<ref>{{cite journal | vauthors = Chen JM, Dando PM, Stevens RA, Fortunato M, Barrett AJ | title = Cloning and expression of mouse legumain, a lysosomal endopeptidase | journal = The Biochemical Journal | volume = 335 ( Pt 1) | issue = 1 | pages = 111–7 | date = October 1998 | pmid = 9742219 | doi = 10.1042/bj3350111 }}</ref> and the protein is mostly localised to [[lysosome]]s and [[endosome]]s. It is also interesting that AEP is activated in age-dependent manner.<ref name="Zhao 2014">{{cite journal | vauthors = Zhao L, Hua T, Crowley C, Ru H, Ni X, Shaw N, Jiao L, Ding W, Qu L, Hung LW, Huang W, Liu L, Ye K, Ouyang S, Cheng G, Liu ZJ | title = Structural analysis of asparaginyl endopeptidase reveals the activation mechanism and a reversible intermediate maturation stage | journal = Cell Research | volume = 24 | issue = 3 | pages = 344–58 | date = March 2014 | pmid = 24407422 | pmc = 3945893 | doi = 10.1038/cr.2014.4 }}</ref> |
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== Activation == |
== Activation == |
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Asparagine endopeptidase is synthesized as an inactive zymogen.<ref>{{cite journal | vauthors = Li DN, Matthews SP, Antoniou AN, Mazzeo D, Watts C | title = Multistep autoactivation of asparaginyl endopeptidase in vitro and in vivo | journal = The Journal of Biological Chemistry | volume = 278 | issue = 40 | pages = 38980–90 | date = October 2003 | pmid = 12860980 | doi = 10.1074/jbc.m305930200 }}</ref> AEP and other cysteine peptidase are activated when pH changes from neutral to acidic. It undergoes [[autoproteolytic maturation]] for catalytic activation. It appears to be autocatalytically cleaved after asparagine or aspartate residue. Activation begins at pH 4.5. The chemical structure at this point shows that breaks which occurs at pH 4.5 can be healed under the basic crystallization conditions. C-terminal fragments (∼13 kDa) generated during autoproteolysis can gradually re-ligated to form the proenzyme when the pH is increased towards pH 7.5, which means that proteolytic activation of AEP can be reversible.<ref name=" |
Asparagine endopeptidase is synthesized as an inactive zymogen.<ref>{{cite journal | vauthors = Li DN, Matthews SP, Antoniou AN, Mazzeo D, Watts C | title = Multistep autoactivation of asparaginyl endopeptidase in vitro and in vivo | journal = The Journal of Biological Chemistry | volume = 278 | issue = 40 | pages = 38980–90 | date = October 2003 | pmid = 12860980 | doi = 10.1074/jbc.m305930200 }}</ref> AEP and other cysteine peptidase are activated when pH changes from neutral to acidic. It undergoes [[autoproteolytic maturation]] for catalytic activation. It appears to be autocatalytically cleaved after asparagine or aspartate residue. Activation begins at pH 4.5. The chemical structure at this point shows that breaks which occurs at pH 4.5 can be healed under the basic crystallization conditions. C-terminal fragments (∼13 kDa) generated during autoproteolysis can gradually re-ligated to form the proenzyme when the pH is increased towards pH 7.5, which means that proteolytic activation of AEP can be reversible.<ref name="Zhao 2014" /> |
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== AEP in neurodegenerative diseases == |
== AEP in neurodegenerative diseases == |
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AEP is activated during [[brain ischemia]] or [[brain acidosis]] and epilepsia seizure. It digests [[Protein SET|SET protein]], which is an inhibitor of [[DNase]], leading to DNA damage and causing damage of the brain. Increased activity of AEP in brain is also observed in patients with [[Alzheimer's disease]] and [[Parkinson's disease]] (PD). AEP cleaves [[Tau protein|tau]] protein and [[amyloid precursor protein]]. In patients with PD, [[Alpha-synuclein|alpha synuclein]] is cut by AEP into toxic chunks.<ref name=" |
AEP is activated during [[brain ischemia]] or [[brain acidosis]] and epilepsia seizure. It digests [[Protein SET|SET protein]], which is an inhibitor of [[DNase]], leading to DNA damage and causing damage of the brain. Increased activity of AEP in brain is also observed in patients with [[Alzheimer's disease]] and [[Parkinson's disease]] (PD). AEP cleaves [[Tau protein|tau]] protein and [[amyloid precursor protein]]. In patients with PD, [[Alpha-synuclein|alpha synuclein]] is cut by AEP into toxic chunks.<ref name="Zhang 2016">{{cite journal | vauthors = Zhang Z, Xie M, Ye K | title = Asparagine endopeptidase is an innovative therapeutic target for neurodegenerative diseases | journal = Expert Opinion on Therapeutic Targets | volume = 20 | issue = 10 | pages = 1237–45 | date = October 2016 | pmid = 27115710 | doi = 10.1080/14728222.2016.1182990 }}</ref> |
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=== AEP in Alzheimer's disease === |
=== AEP in Alzheimer's disease === |
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Active AEP was found at increased levels and translocated to the [[cytoplasm]] of neuronal cells of AD patients.<ref>{{cite journal | vauthors = Basurto-Islas G, Grundke-Iqbal I, Tung YC, Liu F, Iqbal K | title = Activation of asparaginyl endopeptidase leads to Tau hyperphosphorylation in Alzheimer disease | journal = The Journal of Biological Chemistry | volume = 288 | issue = 24 | pages = 17495–507 | date = June 2013 | pmid = 23640887 | pmc = 3682549 | doi = 10.1074/jbc.M112.446070 }}</ref> In AD the plaques are composed of [[amyloid beta]], intracellular neurofibrillary tangles and tau protein. The dysfunction of APP proteolysis and the abnormal phosphorylation of tau lead to the formation of neuritic plaques and neurofibrillary tangles (NFTs), respectively, causing [[Neurodegeneration|neuronal degeneration]] and [[dementia]]<ref>{{cite journal | vauthors = Zhang Z, Song M, Liu X, Kang SS, Kwon IS, Duong DM, Seyfried NT, Hu WT, Liu Z, Wang JZ, Cheng L, Sun YE, Yu SP, Levey AI, Ye K | title = Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer's disease | journal = Nature Medicine | volume = 20 | issue = 11 | pages = 1254–62 | date = November 2014 | pmid = 25326800 | pmc = 4224595 | doi = 10.1038/nm.3700 }}</ref> It also play a crucial role in behavior disorders connected with AD such as anxiety and depression. It also plays a role in stroke. Since stroke elicits acidity in the brain AEP become active due to low pH level. Then it cleaves SET which causes death of brain cells.<ref>{{cite journal | vauthors = Gao J, Li K, Du L, Yin H, Tan X, Yang Z | title = Deletion of asparagine endopeptidase reduces anxiety- and depressive-like behaviors and improves abilities of spatial cognition in mice | journal = Brain Research Bulletin | volume = 142 | pages = 147–155 | date = July 2018 | pmid = 30030107 | doi = 10.1016/j.brainresbull.2018.07.010 }}</ref> Targeting of AEP might help to prevent onset of AD symptoms. Development of AEP-selective inhibitors (such as Cbz-L-Ala-L-Ala-AzaAsnchloromethylketone and aza-peptidyl AEP inhibitors) is crucial for helping with diseases.<ref name=" |
Active AEP was found at increased levels and translocated to the [[cytoplasm]] of neuronal cells of AD patients.<ref>{{cite journal | vauthors = Basurto-Islas G, Grundke-Iqbal I, Tung YC, Liu F, Iqbal K | title = Activation of asparaginyl endopeptidase leads to Tau hyperphosphorylation in Alzheimer disease | journal = The Journal of Biological Chemistry | volume = 288 | issue = 24 | pages = 17495–507 | date = June 2013 | pmid = 23640887 | pmc = 3682549 | doi = 10.1074/jbc.M112.446070 }}</ref> In AD the plaques are composed of [[amyloid beta]], intracellular neurofibrillary tangles and tau protein. The dysfunction of APP proteolysis and the abnormal phosphorylation of tau lead to the formation of neuritic plaques and neurofibrillary tangles (NFTs), respectively, causing [[Neurodegeneration|neuronal degeneration]] and [[dementia]]<ref>{{cite journal | vauthors = Zhang Z, Song M, Liu X, Kang SS, Kwon IS, Duong DM, Seyfried NT, Hu WT, Liu Z, Wang JZ, Cheng L, Sun YE, Yu SP, Levey AI, Ye K | title = Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer's disease | journal = Nature Medicine | volume = 20 | issue = 11 | pages = 1254–62 | date = November 2014 | pmid = 25326800 | pmc = 4224595 | doi = 10.1038/nm.3700 }}</ref> It also play a crucial role in behavior disorders connected with AD such as anxiety and depression. It also plays a role in stroke. Since stroke elicits acidity in the brain AEP become active due to low pH level. Then it cleaves SET which causes death of brain cells.<ref>{{cite journal | vauthors = Gao J, Li K, Du L, Yin H, Tan X, Yang Z | title = Deletion of asparagine endopeptidase reduces anxiety- and depressive-like behaviors and improves abilities of spatial cognition in mice | journal = Brain Research Bulletin | volume = 142 | pages = 147–155 | date = July 2018 | pmid = 30030107 | doi = 10.1016/j.brainresbull.2018.07.010 }}</ref> Targeting of AEP might help to prevent onset of AD symptoms. Development of AEP-selective inhibitors (such as Cbz-L-Ala-L-Ala-AzaAsnchloromethylketone and aza-peptidyl AEP inhibitors) is crucial for helping with diseases.<ref name="Zhang 2016" /> |
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== AEP in immune system == |
== AEP in immune system == |
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There are many regulators which affect [[immune system]] and help to keep it balanced. If the immune system is too active there is a danger of developing an autoimmune disease, while passive immune system will lead to infections or cancer. [[Antigen-presenting cell|Antigen presenting]] is a key role in activation of immune system.<ref name=" |
There are many regulators which affect [[immune system]] and help to keep it balanced. If the immune system is too active there is a danger of developing an autoimmune disease, while passive immune system will lead to infections or cancer. [[Antigen-presenting cell|Antigen presenting]] is a key role in activation of immune system.<ref name="Zhang 2016" /> It has been discovered that AEP plays role in this critical moment. AEP is involved is presenting of foreign and self proteins using [[MHC class II|MHCII protein complex]].<ref>{{cite journal | vauthors = Matthews SP, Werber I, Deussing J, Peters C, Reinheckel T, Watts C | title = Distinct protease requirements for antigen presentation in vitro and in vivo | journal = Journal of Immunology | volume = 184 | issue = 5 | pages = 2423–31 | date = March 2010 | pmid = 20164435 | doi = 10.4049/jimmunol.0901486 }}</ref> The role of AEP in immunity is not clear, but it seems that it is connected with checkpoint inhibitors such as [[Programmed cell death protein 1|PD-1]], which downregulates AEP which is key to shifting the balance between cancer fighting cells and [[regulatory T cell]]s. In the absence of AEP, inhibitory checkpoints may not have a beneficial response. Measuring of this enzyme in patients could predict which one of them may provide better response to treatment.<ref>{{Cite news|url=https://medicalxpress.com/news/2018-07-enzyme-aep-importance-immunity.html|title=Enzyme AEP's importance to immunity discovered|access-date=2018-08-28}}</ref> |
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=== Antimicrobial activity === |
=== Antimicrobial activity === |
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=== Signalling === |
=== Signalling === |
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In innate immunity [[Toll-like receptor|TLRs]] play an important role. These TLRs (mainly [[TLR7]] and [[TLR9]]) can be proteolytically activated by AEP.<ref name=" |
In innate immunity [[Toll-like receptor|TLRs]] play an important role. These TLRs (mainly [[TLR7]] and [[TLR9]]) can be proteolytically activated by AEP.<ref name="Maschalidi 2012">{{cite journal | vauthors = Maschalidi S, Hässler S, Blanc F, Sepulveda FE, Tohme M, Chignard M, van Endert P, Si-Tahar M, Descamps D, Manoury B | title = Asparagine endopeptidase controls anti-influenza virus immune responses through TLR7 activation | journal = PLoS Pathogens | volume = 8 | issue = 8 | pages = e1002841 | date = 2012-08-16 | pmid = 22916010 | doi = 10.1371/journal.ppat.1002841 }}</ref> The reduction of proinflammatory [[cytokine]]s by stimulating TLR9 was found in [[Myelocyte|myeloid cells]] and [[plasmacytoid dendritic cell]]s which lacked AEP.<ref>{{cite journal | vauthors = Sepulveda FE, Maschalidi S, Colisson R, Heslop L, Ghirelli C, Sakka E, Lennon-Duménil AM, Amigorena S, Cabanie L, Manoury B | title = Critical role for asparagine endopeptidase in endocytic Toll-like receptor signaling in dendritic cells | journal = Immunity | volume = 31 | issue = 5 | pages = 737–48 | date = November 2009 | pmid = 19879164 | doi = 10.1016/j.immuni.2009.09.013 }}</ref> Enzyme is also important in processing of [[influenza virus]] and immune response using TLR7.<ref name="Maschalidi 2012"/> AEP plays a critical role in TLR processing. and AEP can initiate removal of [[CD74|invariant chain]] in MHC-II complex, which can critically influence peptide generation and activity of MHCII.<ref>{{cite journal | vauthors = Manoury B, Mazzeo D, Li DN, Billson J, Loak K, Benaroch P, Watts C | title = Asparagine endopeptidase can initiate the removal of the MHC class II invariant chain chaperone | journal = Immunity | volume = 18 | issue = 4 | pages = 489–98 | date = April 2003 | pmid = 12705852 | doi = 10.1016/s1074-7613(03)00085-2 }}</ref> |
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== References == |
== References == |
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Revision as of 06:17, 18 May 2019
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Asparagine endopeptidase (AEP, mammalian legumain) is a proteolytic enzyme from C13 peptidase family which hydrolyses a peptide bond using the thiol group of a cysteine residue as a nucleophile (hence also called cysteine protease). It hydrolyzes substrates at the C-terminus of asparagine residues. Discovered in 1996 in beans, its homologues have been identified in plants, protozoa, vertebrates, and helminths. The enzyme has been implicated in several human diseases such as cancer, atherosclerosis and inflammation .[1] It can be detected in spleen, liver, brain, testis tissue and heart[2] and the protein is mostly localised to lysosomes and endosomes. It is also interesting that AEP is activated in age-dependent manner.[3]
Activation
Asparagine endopeptidase is synthesized as an inactive zymogen.[4] AEP and other cysteine peptidase are activated when pH changes from neutral to acidic. It undergoes autoproteolytic maturation for catalytic activation. It appears to be autocatalytically cleaved after asparagine or aspartate residue. Activation begins at pH 4.5. The chemical structure at this point shows that breaks which occurs at pH 4.5 can be healed under the basic crystallization conditions. C-terminal fragments (∼13 kDa) generated during autoproteolysis can gradually re-ligated to form the proenzyme when the pH is increased towards pH 7.5, which means that proteolytic activation of AEP can be reversible.[3]
AEP in neurodegenerative diseases
AEP is activated during brain ischemia or brain acidosis and epilepsia seizure. It digests SET protein, which is an inhibitor of DNase, leading to DNA damage and causing damage of the brain. Increased activity of AEP in brain is also observed in patients with Alzheimer's disease and Parkinson's disease (PD). AEP cleaves tau protein and amyloid precursor protein. In patients with PD, alpha synuclein is cut by AEP into toxic chunks.[1]
AEP in Alzheimer's disease
Active AEP was found at increased levels and translocated to the cytoplasm of neuronal cells of AD patients.[5] In AD the plaques are composed of amyloid beta, intracellular neurofibrillary tangles and tau protein. The dysfunction of APP proteolysis and the abnormal phosphorylation of tau lead to the formation of neuritic plaques and neurofibrillary tangles (NFTs), respectively, causing neuronal degeneration and dementia[6] It also play a crucial role in behavior disorders connected with AD such as anxiety and depression. It also plays a role in stroke. Since stroke elicits acidity in the brain AEP become active due to low pH level. Then it cleaves SET which causes death of brain cells.[7] Targeting of AEP might help to prevent onset of AD symptoms. Development of AEP-selective inhibitors (such as Cbz-L-Ala-L-Ala-AzaAsnchloromethylketone and aza-peptidyl AEP inhibitors) is crucial for helping with diseases.[1]
AEP in immune system
There are many regulators which affect immune system and help to keep it balanced. If the immune system is too active there is a danger of developing an autoimmune disease, while passive immune system will lead to infections or cancer. Antigen presenting is a key role in activation of immune system.[1] It has been discovered that AEP plays role in this critical moment. AEP is involved is presenting of foreign and self proteins using MHCII protein complex.[8] The role of AEP in immunity is not clear, but it seems that it is connected with checkpoint inhibitors such as PD-1, which downregulates AEP which is key to shifting the balance between cancer fighting cells and regulatory T cells. In the absence of AEP, inhibitory checkpoints may not have a beneficial response. Measuring of this enzyme in patients could predict which one of them may provide better response to treatment.[9]
Antimicrobial activity
AEP or legumain is used in African medicine. In plant Oldenlandia affinis it has shown antimicrobial activity by generating cyclic peptides which are important for defence against pathogens in plants. The herb has been used in native African medicine to accelerate childbirth.[10][11]
Signalling
In innate immunity TLRs play an important role. These TLRs (mainly TLR7 and TLR9) can be proteolytically activated by AEP.[12] The reduction of proinflammatory cytokines by stimulating TLR9 was found in myeloid cells and plasmacytoid dendritic cells which lacked AEP.[13] Enzyme is also important in processing of influenza virus and immune response using TLR7.[12] AEP plays a critical role in TLR processing. and AEP can initiate removal of invariant chain in MHC-II complex, which can critically influence peptide generation and activity of MHCII.[14]
References
- ^ a b c d Zhang Z, Xie M, Ye K (October 2016). "Asparagine endopeptidase is an innovative therapeutic target for neurodegenerative diseases". Expert Opinion on Therapeutic Targets. 20 (10): 1237–45. doi:10.1080/14728222.2016.1182990. PMID 27115710.
- ^ Chen JM, Dando PM, Stevens RA, Fortunato M, Barrett AJ (October 1998). "Cloning and expression of mouse legumain, a lysosomal endopeptidase". The Biochemical Journal. 335 ( Pt 1) (1): 111–7. doi:10.1042/bj3350111. PMID 9742219.
- ^ a b Zhao L, Hua T, Crowley C, Ru H, Ni X, Shaw N, Jiao L, Ding W, Qu L, Hung LW, Huang W, Liu L, Ye K, Ouyang S, Cheng G, Liu ZJ (March 2014). "Structural analysis of asparaginyl endopeptidase reveals the activation mechanism and a reversible intermediate maturation stage". Cell Research. 24 (3): 344–58. doi:10.1038/cr.2014.4. PMC 3945893. PMID 24407422.
- ^ Li DN, Matthews SP, Antoniou AN, Mazzeo D, Watts C (October 2003). "Multistep autoactivation of asparaginyl endopeptidase in vitro and in vivo". The Journal of Biological Chemistry. 278 (40): 38980–90. doi:10.1074/jbc.m305930200. PMID 12860980.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Basurto-Islas G, Grundke-Iqbal I, Tung YC, Liu F, Iqbal K (June 2013). "Activation of asparaginyl endopeptidase leads to Tau hyperphosphorylation in Alzheimer disease". The Journal of Biological Chemistry. 288 (24): 17495–507. doi:10.1074/jbc.M112.446070. PMC 3682549. PMID 23640887.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Zhang Z, Song M, Liu X, Kang SS, Kwon IS, Duong DM, Seyfried NT, Hu WT, Liu Z, Wang JZ, Cheng L, Sun YE, Yu SP, Levey AI, Ye K (November 2014). "Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer's disease". Nature Medicine. 20 (11): 1254–62. doi:10.1038/nm.3700. PMC 4224595. PMID 25326800.
- ^ Gao J, Li K, Du L, Yin H, Tan X, Yang Z (July 2018). "Deletion of asparagine endopeptidase reduces anxiety- and depressive-like behaviors and improves abilities of spatial cognition in mice". Brain Research Bulletin. 142: 147–155. doi:10.1016/j.brainresbull.2018.07.010. PMID 30030107.
- ^ Matthews SP, Werber I, Deussing J, Peters C, Reinheckel T, Watts C (March 2010). "Distinct protease requirements for antigen presentation in vitro and in vivo". Journal of Immunology. 184 (5): 2423–31. doi:10.4049/jimmunol.0901486. PMID 20164435.
- ^ "Enzyme AEP's importance to immunity discovered". Retrieved 2018-08-28.
- ^ Gillon AD, Saska I, Jennings CV, Guarino RF, Craik DJ, Anderson MA (February 2008). "Biosynthesis of circular proteins in plants". The Plant Journal. 53 (3): 505–15. doi:10.1111/j.1365-313x.2007.03357.x. PMID 18086282.
- ^ Craik DJ (February 2012). "Host-defense activities of cyclotides". Toxins. 4 (2): 139–56. doi:10.3390/toxins4020139. PMID 22474571.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ a b Maschalidi S, Hässler S, Blanc F, Sepulveda FE, Tohme M, Chignard M, van Endert P, Si-Tahar M, Descamps D, Manoury B (2012-08-16). "Asparagine endopeptidase controls anti-influenza virus immune responses through TLR7 activation". PLoS Pathogens. 8 (8): e1002841. doi:10.1371/journal.ppat.1002841. PMID 22916010.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Sepulveda FE, Maschalidi S, Colisson R, Heslop L, Ghirelli C, Sakka E, Lennon-Duménil AM, Amigorena S, Cabanie L, Manoury B (November 2009). "Critical role for asparagine endopeptidase in endocytic Toll-like receptor signaling in dendritic cells". Immunity. 31 (5): 737–48. doi:10.1016/j.immuni.2009.09.013. PMID 19879164.
- ^ Manoury B, Mazzeo D, Li DN, Billson J, Loak K, Benaroch P, Watts C (April 2003). "Asparagine endopeptidase can initiate the removal of the MHC class II invariant chain chaperone". Immunity. 18 (4): 489–98. doi:10.1016/s1074-7613(03)00085-2. PMID 12705852.